Herpesvirus pathogens establish life-long infections in their host, and the human gammaherpesviruses are leading agents of viral-associated cancers. An understanding of the molecular mechanisms used by gammaherpesviruses to promote latency is key to effective intervention. The broad objective of this proposal is to identiy virus-host interactions that are critical for the establishment and maintenance of latent infections. The murine gammaherpesvirus (MHV68) is a valuable model for pathogenesis that can be used to identify and investigate virus-host interactions that are critical for chronic gamma herpesvirus infection in vivo. Exciting preliminary results with infection of mice reveals the host signal transducer and activator of transcription 3, STAT3, is needed to promote MHV68 latency. Animals that have a conditional deletion of the STAT3 gene are defective for establishment of a latent infection in primary B cells. STAT3 supports cell survival and proliferation, and is causall linked to many cancers. However, little is known regarding how STAT3 contributes to the initial events of viral infection in B cells in the context of the host. Our central hypothesis is that gammaherpesviruses need STAT3 to promote B cell latency, and the viral transactivator RTA antagonizes STAT3 function to promote the initiation of productive replication. This proposal describes innovative, high-impact experimental approaches to elucidate the contribution of STAT3 to gammaherpesvirus latency, and, in turn, how the virus modulates STAT3 to promote infection. In Aim 1, the role of STAT3 in a pathogenic model system of gammaherpesvirus infection will be determined by examining the ability of MHV68 to establish and maintain latency in the presence or absence of STAT3. The STAT3-dependent cellular gene network that mediates latency will be determined. In Aim 2, we will define the mechanisms by which RTA modulates STAT3. Functional motifs required for STAT3 action will be identified, and the viral gene targets of STAT3 that influence the latent or lytic outcome of infection in culture and in the infected animal will be determined. These mechanistic investigations of the host:virus interface in the context of a gammaherpesvirus infection in a natural host will provide significant insight a to how gammaherpesviruses differentially use and subvert host signaling processes during latency and productive infection.